Method for the treatment of depression

ABSTRACT

The invention relates to the use of compounds which act as antagonists of 5-hydroxytryptamine (5-HT) at 5-HT 3  receptors for the treatment of depression.

This application is a division of application Ser. No. 07/912,337, filedJul. 13, 1992, which is a continuation of application Ser. No.07/723,264 filed Jun. 28, 1991, now abandoned, which is a continuationof application Ser. No. 07/522,321, filed May 11, 1990, now abandoned,which is a divisional application of application Ser. No. 07/133,896,filed Dec. 16, 1987, now U.S. Pat. No. 4,973,594, issued Nov. 27,1990.

This invention relates to a new medical use for certain chemicalcompounds and pharmaceutical compositions containing them. In particularit relates to the use in the treatment of depression of compounds whichact as antagonists of 5-hydroxytryptamine (5-HI) at receptors known inthe art as 5-HT₃, 5-HT`M` or 5-HI `M`-like' receptors. Such receptorshave been described for example by Forzard et al., Eur. J. Pharmacol.,1979, 59, 195-210; Ireland, Straughan and Tyers, Br. J. Pharmacol.,1982, 75, 16P; Humphrey, Neuropharm., 1984, 23, 1503-1570; Richardson etal., Nature, 1985, 316, 126-131; and Bradley et al., Neuropharm., 1986,25, 563-576. Receptors of this type are now designated as 5-HT₃receptors.

5-HT receptors of this type are located, for example, on the terminalsof afferent sensory neurones, in the isolated guinea-pig ileumpreparation and are also present in the central nervous system.Compounds which act an antagonists of 5-HT at 5-HT₃ receptors may beidentified using standard tests, for example, in vitro by measuringtheir inhibition of the depolarising effect of 5-HT on the rat or rabbitisolated vagus nerve, or the tachycardia produced by 5-HT in the rabbitisolated heart or the contraction produced by 5-HT in the guinea-pigisolated ileum, or in vivo by measuring their effect on the VonBezold-Jarisch reflex (induced by 5-HT) as described, for example, inthe above-mentioned references.

A variety of compounds which act as antagonists of 5-HT at 5-HT₃receptors have been described in the art. These compounds are generallyazabicyclo derivatives and/or benzoic acid derivatives, or imidazolederivatives. The azabicyclo derivatives include compounds containing abridged piperidyl group, such as a tropyl, pseudotropyl, homotropyl orquinucilindyl group, and they preferably contain a carbocyclic orheterocyclic aromatic group linked, for example as an ester or amide, tothe azabicyclic ring. The aromatic group may be for example anoptionally substituted phenyl, indolyl, benzofuranyl, benzothienyl,benzisoxazolyl, indazolyl or pyrimidinyl group.

The benzoic acid derivatives when act as antagonists of 5-HI at 5-HT₃receptors include benzoates and benzamides, for example esters or amidesformed with an azabicyclic group as defined above, or formed with apiperidyl group.

Such compounds have been disclosed inter alia in published UK PatentApplications Nos. 2100259, 2125398. 2131420, 2132189, 2145416, 2152049,2153821 and 2169292, published European Patent Applications Nos. 111608,116255, 158265, 191562, 200444, 210840, 214772, 219193, 221702, 226267,227215, 230718, 235878 and 242973, and published Australian PatentApplication No. 87/67121. The compounds disclosed in published EuropeanPatent Application Nos. 13138, 67615, and 94742 have also been describedas antagonists of 5-HT at 5-HT₃ receptors in published European PatentApplications Nos. 215545 and 220011. In addition4-amino-N-1-azabicyclo[2.2.2]oct-3-yl-5-chloro-2-methoxy benzamide (alsoknown as zacopride), described in European Patent Specification No.99789, has also now been shown to be an antagonist of 5-HT at 5HT₃receptors.

The compounds disclosed in these specifications have been described asbeing of use in a variety of conditions, including migraine.

We have now found that compounds which act as 5-HT antagonists at 5-HT₃receptors may be used in the treatment of depression.

1,2,3,9-Tetrahydro-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-4H-carbazol-4-oneand its salts and solvates, which are disclosed in published UK PatentApplication No. 2153821A are however excluded from the presentinvention. It will be appreciated that general references hereinafter to"compounds which act as antagonists of 5-HT at 5-HT₃ receptors" and tothose compounds "disclosed in published UK Patent Application No.2153821A" exclude1,2,3,9-tetrahydro-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-4H-carbazol-4-oneand its salts and solvates.

Accordingly the invention provides a method of treatment of a subject,in particular a human subject, suffering from depression which comprisesadministering to the subject an effective amount of a compound whichacts as an antagonist of 5-HT at 5-HT₃ receptors, or a physiologicallyacceptable salt or solvate thereof.

References in this specification to treatment include prophylactictreatment as well as the acute alleviation of symptoms.

Preferred 5-HT₃ receptor antagonists for use in the present inventionare azabicyclo derivatives (e.g. containing a bridged piperidyl groupsuch as a tropyl, pseudotropyl, homotropyl of quinuclidinyl group andbenzoic acid derivatives (e.g. benzoates and benzamides). Furtherpreferred 5-HT₃ receptor antagonists for use in the present inventionare 3-(imidazol-1-yl)methyltetrahydrocarbazolones and3-(imidazol-4-yl)-(indol-3-yl)-1-propanones.

Particular mention may be made of the compounds which act as antagonistsof 5-HT at 5-HT₃ receptors disclosed in published UK PatentSpecification Nos. 2100259, 2125398, 2131420, 2132189, 2145416, 2152049,2153821 and 2169292, published European Patent Specification Nos. 13138,67615, 94742, 99789, 111608, 116255, 158265, 191562, 200444, 210840,214772, 219193, 221702, 226267, 227215, 230718, 235878 and 242973, andpublished Australian Patent Application No. 87/67121.

Preferred compounds for use according to the invention are thosecompounds which act as antagonists of 5-HT at 5-HT₃ receptors describedin published UK Patent Specification Nos. 2100259, 2132189, 2125398,2152049 and 2153821, published European Patent Specification Nos. 13138,94742, 99789, 116255, 200444, 221702, 226267, 235878 and 242973 andpublished Australian Patent Application No. 87/67121.

Particularly preferred compounds for use according to the presentinvention are those described in published UK Patent Specification Nos.2100259 and 2125398 and published UK Patent Specification Nos. 94742,200444 and 242973. A further particularly preferred compound for useaccording to the invention is zacopride.

A preferred group of compounds for use according to the invention,described in UK Specification No. 2125398, may be represented by thegeneral formula (I): ##STR1## wherein

R₁ and R₂ independently represent hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy, amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, mercapto orC₁₋₄ alkylthio;

R₃ represents hydrogen, C₁₋₄ alkyl, C₃₋₅ alkenyl, aryl or aralkyl;

R₄ represents hydrogen, C₁₋₇ alkyl, C₃₋₅ alkenyl or aralkyl;

n is 2 or 3;

the free valence is attached to either fused ring, and the azabicyclicring is in either the exo or endo configuration; and acid addition saltsand quaternary ammonium salts thereof.

In the compounds of formula (I) R₁ and R₂ may, for example,independently represent hydrogen, halogen or C₁₋₄ alkyl, R₃ may be, forexample, hydrogen or C₁₋₄ alkyl and R₄ may be, for example, hydrogen,C₁₋₇ alkyl or aralkyl, the carbonyl group is preferably attached to the3-positioned of the indole ring, and the azabicyclic ring is preferablyin the endo configuration.

Another preferred group of compounds for use according to the invention,described in UK Specification No. 2100259, may be represented by thegeneral formula (II): ##STR2## wherein R₅ represents C₁₋₄ alkyl, C₁₋₄alkoxy, or halogen; and R₆ and R₇ independently represent hydrogen, C₁₋₄alkyl, C₁₋₄ alkoxy or halogen provided that R₆ is hydrogen when R₇ ishydrogen; and pharmaceutically acceptable salts thereof. A preferredclass of compounds of formula (II) are those in which R₅ and R₇ are thesame and each represents methyl, methoxy or chlorine, and R₆ representshydrogen.

A further preferred group of compounds for use according to theinvention, described in European Specification No. 94742, may berepresented by the general formula (III): ##STR3## wherein

R₈ presents a C₁₋₆ alkoxy or amino N-substituted by one or two groupsselected from C₁₋₆ alkyl or C₃₋₈ cycloalkyl or optionally N-substitutedby C₄₋₅ polymethylene;

one of R₉, R₁₀ and R₁₁ is hydrogen and the other two are independentlyselected from hydrogen, chloro, bromo, trifluoromethyl, hydroxy, C₁₋₆alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl and amino;

one of R₁₂ and R₁₃ represents hydrogen, C₁₋₆ alkyl, phenyl or phenylC₁₋₃ alkyl, which phenyl moieties may be substituted by C₁₋₆ alkyl, C₁₋₆alkoxy, CF₃ or halogen, and the other of R₁₂ and R₁₃ is hydrogen or C₁₋₆alkyl;

q is zero or an integer from 1 to 4;

r is zero, or an integer from 1 to 3; and

s is zero, 1 or 2.

Preferred compounds of formula (III) are those wherein R₈ is methoxy, R₉is hydrogen, R₁₀ is 4-amino, R₁₁ is 5-chloro (relative to the benzamidegroup),

R₁₂ and R₁₃ independently represent hydrogen or C₁₋₆ alkyl;

q is zero, r is 1 or 2 and s is zero, 1 or 2.

Yet another preferred group of compounds for use according to theinvention, described in European Specification No. 200444, may berepresented by the general formula (IV): ##STR4## wherein

X is CO and Y is NH or O; and

p is 2 or 3;

and pharmaceutically acceptable salts thereof.

A still further preferred group of compounds for use according to theinvention, described in our UK Patent Specification No. 2153821 andEuropean Specifications Nos. 191562, 210840 and 219193, may berepresented by the general formula (V): ##STR5## wherein

R¹⁴ represents a hydrogen atom or a group selected from C₁₋₁₀ alkyl,C₃₋₆ alkenyl, C₃₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₄alkyl, phenyl or phenyl C₁₋₃ alkyl, and in the case where Q represents ahydrogen atom, R¹⁴ may also represent --CO₂ R¹⁸, -COR¹⁸, --CONR¹⁸ R¹⁹ or--SO₂ R¹⁸ (wherein R¹⁸ and R¹⁹, which may be the same or different, eachrepresents a hydrogen atom, a C₁₋₆ alkyl or C₃₋₇ cycloalkyl group, or aphenyl or phenyl C₁₋₄ alkyl group, in which the phenyl group isoptionally substituted by one or more C₁₋₄ alkyl, C₁₋₄ alkoxy or hydroxygroups or halogen atoms, with the proviso that R¹⁸ does not represent ahydrogen atom when R¹⁴ represents a group --CO₂ R¹⁸ or --SO₂ R¹⁸);

one of the groups represented by R¹⁵, R¹⁶ and R¹⁷ is a hydrogen atom ora C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, or phenyl C₁₋₃ alkyl group,and each of the other two groups, which may be the same or different,represents a hydrogen atom or a C₁₋₆ alkyl group;

Q represents a hydrogen atom or a halogen atom or a hydroxy, C₁₋₄alkoxy, phenyl C₁₋₃ alkoxy or C₁₋₆ alkyl group or a group --NR²⁰ R²¹ or--CONR²⁰ R²¹ (wherein R²⁰ and R²¹, which may be the same or different,each represents a hydrogen atom or a C₁₋₄ alkyl or C₃₋₄ alkenyl group,or together with the nitrogen atom to which they are attached form asaturated 5 to 7 membered ring);

and physiologically acceptable salts and solvates thereof.

A preferred class of compounds represented by the formula (V) for useaccording to the present invention is that wherein R¹⁴ represents ahydrogen atom or a methyl, ethyl, propyl, prop-2-yl, prop-2-enyl orcyclopentyl group; R¹⁶ represents a hydrogen atom; and either R¹⁵represents a methyl, ethyl, propyl or prop-2-yl group and R¹⁷ representsa hydrogen atom or R¹⁵ represents a hydrogen atom and R¹⁷ represents amethyl or ethyl group; and Q represents a hydrogen atom.

Another preferred group of compounds for use according to the invention,described in European Patent Specification No. 242973, may berepresented by the general formula (VI): ##STR6## wherein Im representsan imidazolyl group of formula: ##STR7##

R²² represents a hydrogen atom or a C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₁₀alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₄ alkyl, phenyl or phenylC₁₋₃ alkyl group;

R²³ represents a hydrogen atom or a C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₇cycloalkyl, phenyl or phenyl C₁₋₃ alkyl group;

R²⁴ and R²⁵, which may be the same or different, each represents ahydrogen atom or a C₁₋₆ alkyl group;

one of the groups represented by R²⁶, R²⁷ and R²⁸, is a hydrogen atom ora C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ alkenyl, phenyl or phenyl C₁₋₃ alkylgroup, and each of the other two groups, which may be the same ordifferent, represents a hydrogen atom or a C₁₋₆ alkyl group; andphysiologically acceptable salts and solvates thereof.

A preferred class of compounds represented by the formula (VI) for useaccording to the present invention are those wherein R²² represents ahydrogen atom or a methyl, prop-2-enyl or cyclpentyl group; R²³represents a hydrogen atom or a methyl group; R²⁴ and R²⁵ eachindependently represent a hydrogen atom or a methyl group; R²⁶ and R²⁷each represent a hydrogen atom; and R²⁸ represents a hydrogen atom or aC₁₋₃ alkyl group, most preferably methyl.

Yet another preferred group of compounds for use according to theinvention, described in European Specification No. 235878 and AustralianSpecification No. 87/67121, may be presented by the general formula(VII) and (VIII) respectively: ##STR8## wherein

L is NH or O;

R²⁹ and R³⁰ are independently selected from hydrogen, halogen, CF₃, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₇ acyl, C₁₋₇ acylamino, C₁₋₆alklsulphonylamino, N-(₁₋₆ alkylsulphonyl)-N-C₁₋₄ alkylamino, C₁₋₆alkylsulphinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl,aminosulphonylamino or N-(aminosulphonyl)-C₁₋₄ alkylamino optionallyN-substituted by one or two groups selected from C₁₋₆ alkyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkyl C₁₋₄ alkyl, phenyl or phenyl C₁₋₄ alkylgroups or optionally N-disubstituted by C₄₋₅ polymethylene;

Z is a moiety capable of hydrogen bonding to the NH group depicted informula (VII);

D and E are independently selected from hydrogen or C₁₋ alkyl, ortogether are a bond;

R³¹ and R³² are independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl C₁₋₄ alkyl, or together are C₂₋₄ polymethylene;

M is a group of formula (a), (b) or (c): ##STR9## wherein t is 2 or 3; uis 1 or 2; v is 1 to 3; w is 1 to 3; and R³³ or R³⁴ is C₁₋₇ alkyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkyl C₁₋₂ alkyl or C₂₋₇ alkenyl C₁₋₄ alkenyl;

and pharmaceutically acceptable salts thereof.

Preferably L is NH; R²⁹ is often hydrogen and R³⁰ is hydrogen or a4-substituent such as halo or methoxy; Z is preferably C--OCH₃, C--OC₂H₅, C--OC₃ H₇, C--CO₂ CH₃, C--CO₂ C₂ H₅ or SO₂ N(CH₃)₂ ; often D and Eare both hydrogen; often R³¹ and R³² are both hydrogen; preferably t is2 or 3 and u, v and w are 1 or 2; and R³³ /R³⁴ is preferably methyl orethyl, most preferably methyl.

A specific compound within general formula (VIII) as described inExample 5 of Australian specification number 87/67121 isendo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3,3-dimethylindole-1-carboxamide.

A further preferred group of compounds for use according to theinvention, described in UK Specification No. 2152049, may be representedby the general formula (IX): ##STR10## wherein R¹, R² and R³ are asdefined for general formula (I) and G is a group of formula (c) or (e):##STR11## wherein R³⁵ is C₁₋₄ alkyl and R³⁶ is methoxy; andpharmaceutically acceptable salts thereof.

Particularly preferred compounds for use according to the presentinvention are (3α-tropanyl)-1H-indole-3-carboxylic acid ester andendo-N-(9-methyl-9-azabicyclo[3,3,1l]non-3-yl)-1-methylindazole-3-carboxamide and physiologically acceptablesalts and solvates thereof.

Other preferred compounds for use according to the present inventionare:

3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone;

4-amino-N-1-azabicyclo[2.2.2]oct-3-yl-5-chloro-2-methoxybenzamide; 1αH,3α,5αH-tropan-3-yl-3,5-dimethylbenzoate; and

(±)-endo-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo)-[3.3.1]-non-4-yl)benzamide, and their physiologically acceptable salts and solvates. Aparticularly preferred form of the last named compound is itshydrochloride hydrate.

Further preferred compounds for use according to the present inventionare:

1αH,3α,5αH-tropan-3-yl-3,5-dichlorobenzoate;

indole-[5-(2-methyl-2-azabicyclo(2.2.2)octyl]-3-carboxylate;

1H-indol-3-yl-carboxylic acid (3R*,4S*)-1-azabicyclo-[2.2.1]hept-3-ylester;

1H-indolyl-3-carboxylic acid 2S-(1-methyl-2-pyrrolidinylmethyl) ester;

4-amino-5-chloro-2-methoxy-N-(3-quinuclidinylmethyl)benzamide;

1-methyl-3-indazolecarboxylic acid(endo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)ester;

(±)4-amino-5-chloro-2-methoxy-N-(6'α-[4'-thia-1'-azabicyclo[3,3,1]nonyl])benzamide;

(±)4-amino-5-chloro-2-methoxy-N-(6'α-[4'-oxa-1'-azabicyclo[3,3,1]nonyl])benzamide;

and physiologically acceptable salts and solvates thereof.

The invention also provides a pharmaceutical composition which comprisesan effective amount of at least one compound (e.g. an azabicycloderivative, a benzoic acid derivative or an imidazole derivative) whichacts as an antagonist of 5-HT₃ receptors. For use in medicine,particularly human medicine, for the treatment of depression.

In a further aspect the invention provides for the use of a compound(e.g. an azabicyclo derivative, a benzoic acid derivative or animidazole derivative) which acts as an antagonist of 5-HT at 5-HT₃receptors for the manufacture of a medicament for the treatment ofdepression.

Pharmaceutical compositions for use according to the present inventionmay be formulated in conventional manner, optionally with one or morephysiologically acceptable carriers and/or excipients. For example, thecompounds described in the aforementioned patent specifications may beformulated in the manner described therein.

Compounds for use according to the present invention may be formulatedfor oral, buccal, parenteral, rectal or transdermal administration or ina form suitable for administration by inhalation or insufflation (eitherthrough the mouth or the nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropyl methylicellulose); fillers (e.g. lactose, microcrystallinecellulose or calcium hydrogen phosphate); lubricants (e.g. magnesiumstearate, talc or silica); disintegrants (e.g. potato starch or sodiumstarch glycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

Compounds for use according to the present invention may be formulatedfor parenteral administration by injection e.g. by bolus injection orcontinuous infusion. Formulations for injection may be presented in unitdosage form e.g. in ampoules or in multi-dose containers, with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsion in oily or aqueous vehicles, and may containformulatory agents such as suspending. stabilising and/or dispersingagents. Alteratively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

The compounds for use according to the present invention may also beformulated in rectal compositions such as suppositories or retentionenemas, e.g. containing conventional suppository bases such as cocoabutter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously,transuctaneously or intramuscularly) or by intramuscular injection.Thus, for example, the compounds for use according to the presentinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

The dose at which the compounds may be administered to man will dependupon the route of administration, the body weight of the patient, theseverity of the conditions to be treated and the potency of thecompounds. For example, the compounds disclosed in the aforementionedpatent specifications may be administered at doses in the rangesspecified therein for the compounds, or at lower doses for example 0.5μg to 20 mg e.g. 0.005-20 mg, preferably 0.05-10 gm per unit dose whichmay be administered, for example, 1 to 4 times per day.

Thus a unit dose of a compound of formula (I) as herein defined maycontain from 0.2 to 250 mg of the active ingredient, and may beadministered for example up to four times per day, such that the overalldaily dose is in the range 0.5 to 500 mg.

A unit dose of a compound of formula (II) as herein defined may containfrom about 0.5 to 100 mg of the active ingredient, usually 1 to 50 mgand preferably 3 to 30 mg, and may be administered, for example, from 1to 4 times per day.

A unit dose of a compound of formula (III) as herein defined may contain0.1 to 20 mg of active ingredient, for example 0.5 to 10 mg, and may beadministered, for example, up to six times per day, such that the totaldaily dose is normally in the range 0.01 to 10 mg/kg.

A unit dose of a compound of formula (IV) as herein defined may contain0.5 to 1000 mg of the active ingredient, for example 1 to 500 mg, andmay be administered, for example, 1 to 4 times per day, such that thetotal daily dose is in the range 0.001 to 50 mg/kg, more usually 0.002to 25 mg/kg.

A unit dose of a compound of formula (V) as herein defined may contain0.05 to 20 mg of the active ingredient, preferably 0.1 to 10 mg, and maybe administered 1 to 4 times per day.

A unit dose of a compound of formula (VI) as herein defined may contain0.001 to 100 mg of the active ingredient, preferably 0.01 to 50 mg, andmay be administered 1 to 4 times per day. This dosage is also applicableto zacopride.

A unit dose of a compound of formula (VII) as herein defined may contain0.05 to 1000 mg of the active ingredient, for example 0.1 to 500 mg, andmay be administered, for example, 1 to 4 times per day, such that thetotal daily dose is in the range 0.0001 to 50 mg/kg, more usually 0.0002to 25 mg/kg.

A unit dose of a compound of formula (VIII) as herein defined maycontain 0.05 to 1000 mg of the active ingredient, for example 0.5 to 500mg, and may be administered, for example, 1 to 4 times per day, suchthat the total daily dose is in the range 0.0001 to 50 mg/kg, moreusually 0.0002 to 25 mg/kg.

A unit dose of a compound of formula (IX) as herein defined may containfrom 0.1 to 250 mg of the active ingredient, and may be administered upto four times per day, such that the overall daily dose is in the range0.5 to 500 mg.

The following examples illustrate pharmaceutical formulations for useaccording to the invention, contained either(3α-tropanyl)-1H-indole-3-carboxylic acid ester or3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone asthe active ingredient.

Other compounds which are antagonists of 5-HT at 5-HT₃ receptors may beformulated in a similar manner.

TABLETS FOR ORAL ADMINISTRATION

Tablets may be prepared by the normal methods such as direct compressionor wet granulation.

The tablets may be film coated with suitable film forming materials,such as hydroxypropyl methylcellulose, using standard techniques.Alteratively the tablets may be sugar coated.

    ______________________________________                                        Direct Compression Tablet                                                                         mg/tablet                                                 ______________________________________                                        Active Ingredient     0.50                                                    Calcium Hydrogen Phosphate BP*                                                                      87.25                                                   Croscarmellose Sodium NF                                                                            1.8                                                     Magnesium Stearate BP 0.45                                                    Compression weight    90.0                                                    ______________________________________                                         *of a grade suitable for direct compression.                             

The active ingredient is passed through a 60 mesh sieve, blended withthe calcium hydrogen phosphate, croscarmellose sodium and magnesiumstearate. The resultant mix is compressed into tablets using a ManestyF3 tablet machine fitted with 5.5 mm, flat bevelled edge punches.

Tablets of other strengths may be prepared by altering the ratio ofactive ingredient to excipients or the compression weight and usingpunches to suit.

CAPSULES

    ______________________________________                                                        mg/capsule                                                    ______________________________________                                        Active Ingredient 0.5                                                         *Starch 1500      98.5                                                        Magnesium Stearate BP                                                                           1.0                                                         Fill Weight       100.0                                                       ______________________________________                                         *A form of directly compressible starch.                                 

The active ingredient is sieved and blended with the excipients. The mixif filled into size No. 2 hard gelatin capsules using suitablemachinery. Other doses may be prepared by altering the fill weight andif necessary changing the capsule size to suit.

SYRUP

This may be either a sucrose or sucrose free presentation.

    ______________________________________                                        Sucrose-Free           mg/5 ml dose                                           ______________________________________                                        Active ingredient           0.5                                               Hydroxypropylmethylcellulose USP                                                                         22.5                                               (viscosity type 4000)                                                         Buffer                                                                        Flavour                                                                       Colour                     as required                                        Preservative                                                                  Sweetener                                                                     Purified Water BP          to 5.0 ml                                          ______________________________________                                    

The hydroxypropylmethylcellulose is dispersed in hot water, cooled andthen mixed with an aqueous solution containing the active ingredient andthe other components of the formulation. The resultant solution isadjusted to volume and mixed. The syrup is clarified by filtration.

INJECTION FOR INTRAVENOUS ADMINISTRATION

    ______________________________________                                                        mg/ml                                                         ______________________________________                                        Active ingredient 0.05      0.5                                               Sodium Chloride BP                                                                              as required                                                                             as required                                       Water for Injection BP to                                                                       1.0 ml    1.0 ml                                            ______________________________________                                    

Sodium chloride may be added to adjust the tonicity of the solution andthe pH may be adjusted, using acid or alkali, to that of optimumstability and/or facilitate solution of the active ingredient.Alternatively suitable buffer salts may be used.

The solution is prepared, clarified and filled into appropriate sizeampoules sealed by fusion of the glass. The injection is sterilised byheating in an autoclave using one of the acceptable cycles.Alternatively the solution may be sterilised by filtration and filledinto sterile ampoules under aseptic conditions. The solution may bepacked under an inert atmosphere of nitrogen or other suitable gas.

SUPPOSITORY

    ______________________________________                                        Active Ingredient      0.5   mg                                               *Witepsol H15 to       1.0   g                                                ______________________________________                                         *Witepsol H15 is a proprietary grade of Adeps Solidus Ph. Eur.           

A suspension of the active ingredient is prepared in the molten Witepsoland filled, using suitable machinery, into 1 q size suppository moulds.

I claim:
 1. A method for the treatment of depression which comprisesadministering to a patient suffering from depression an effective amountofendo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3,3-dimethylindole-1-carboxamide,or a physiologically acceptable salt or solvate thereof, which compoundacts as a 5-HT antagonist at 5-HT₃ receptors.